Joanna Peris, Kevin J. Anderson, Thomas W. Vickroy , Michael. A. King, Bruce E. Hunter and Don W. Walker

4. CET-INDUCED CHANGES IN GLUTAMATE TRANSMISSION IN HIPPOCAMPUS

There is now more known about the molecular mechanisms important in the induction of the synaptic component of LTP in the CA1 region although there is still much controversy as to whether presynaptic (46) or postsynaptic (47) mechanisms are involved. Both activation of NMDA receptors (see 48) as well as inactivation of GABA receptors (49) appear to be important in the generation and maintenance of LTP although the interplay between these two processes has not been well-defined. The trigger for the induction of LTP is at the NMDA receptor/ion channel complex (see 50). The NMDA receptor can be composed of a mix of 7 splice variants of the NR1 protein subunit with one of four NR2 subunits thereby providing the possibility for functionally distinct receptor subtypes (see 51). Mice lacking a particular subtype of one of the protein subunits that comprise the NMDA receptor exhibit reduced LTP (52). The NMDA receptor is coupled to a nonspecific cation channel which can allow significant transmembrane calcium ion (Ca²⁺) flux. This transient Ca²⁺ may trigger one or more Ca²⁺-dependent enzymes such as Ca²⁺/CAM kinase II, protein kinase C or proteases. One or all of these enzymes may play a critical role in the mechanisms underlying the enhancement of synaptic transmission.

Acute ethanol treatment has been shown to completely block LTP via a direct effect on NMDA-receptor mediated currents (53). Acute ethanol quite potently inhibits NMDA receptor function thereby decreasing Ca²⁺ influx in hippocampus as measured by electrophysiology, Ca²⁺ fluorescence and ⁴⁵Ca²⁺ uptake (54-56). The sensitivity of NMDA receptors to ethanol depends on receptor composition (57, 58). Subchronic repeated exposure to ethanol increases glutamate (59, 60) and NMDA binding sites (61-63) as well as NR1 receptor subunit immunoreactivity in hippocampus (64). Functionally, NMDA-stimulated Ca²⁺ uptake is increased after subchronic repeated ethanol treatment (65, 66) but there is no change in ethanol inhibition of NMDA receptor function (67). Thus, following subchronic ethanol exposure, there is an up-regulation of NMDA receptor number but no change in receptor function. It is important to distinguish that these studies measured the effects of fairly short-term ethanol exposure (days to weeks) and that after withdrawal from ethanol, NMDA receptors usually returned to normal.

It is not clear whether similar changes in NMDA receptor number and function would occur in hippocampus following withdrawal after long-term CET (e.g., 6 months). There is no change in the number or affinity of [³H]MK-801 binding sites, nor is enhancement of this specific binding by glutamate affected by CET (68). These data support the hypothesis that the CET-induced decrease in LTP is not due to a change in NMDA receptor number. In agreement with these data, Northern blot analysis of NR1 mRNA levels in hippocampus indicate no effect of CET (69). These results suggest that although NMDA receptor number and mRNA levels may be altered after short-term exposure to ethanol, these changes do not occur after withdrawal from long-term CET. It will also be important to determine whether the functional status of the NMDA receptor is not altered after CET as well as whether presynaptic indices of glutamate transmission are altered by CET.